Science asks authors to retract XMRV/CFS paper

The study by Lombardi et al. (1) attracted considerable attention, and its publication in Science has had a far-reaching impact on the community of CFS patients and beyond. Because the validity of the study by Lombardi et al. is now seriously in question, we are publishing this Expression of Concern and attaching it to Sciences 23 October 2009 publication by Lombardi et al. The U.S. National Institutes of Health is sponsoring additional carefully designed studies to ascertain whether the association between XMRV and CFS can be confirmed. Science eagerly awaits the outcome of these further studies and will take appropriate action when their results are known.

Thinking about it further... The only action that it appears the Science editorial team are going to take is that they are going to publish an 'editorial expression of concern'... This suggests that they do not have a reason to retract the paper... I think to retract it, they would need proof of contamination or proof that XMRV is not a human virus. (Or evidence of scientific misconduct, but that's not part of the picture.)

Even with the two big new negative studies about to be published, it appears that there still is not enough evidence to prove that the WPI study was invalid.

Click to expand...

We'll see how this all turns out..Science took a big step - publically calling for the authors to retract the paper - but as you noted they did not go the full route and retract it themselves. After the WPI declined to retract the paper the editors certainly had the opportunity to say - we asked and they refused - so we'll retract it. They haven't done that - so they are keeping the door open...

In their Expression of Concern they basically say we have serious doubts about the paper - but that they too are awaiting the results of the Lipkin and BWG studies....the door is still open at Science.

I think by attaching the Expression of Concern to the original paper they are basically stating that there are enough doubts about XMRV that they, as the original publishers of the article new research, feel that they have an obligation to inform other researchers about this (as if they didn't know), and that they believe that no new research should start on XMRV until the NIH studies resolve the issue. They are not saying XMRV is dead....

They're in a kind of strange position....they've asked the authors to retract the article but they won't do it! ..I'm not sure of the logic of that.

I agree that we should be careful. However, scientists like Ruscetti and Alter have good reputations as well. For me this isn't over yet.

Click to expand...

It's not over, but I don't think we can look at all the publicly available data and act like it's likely the WPI's finding is going to hold up.

It would be interesting to hear Ruscetti's thoughts on all this.

I wish we had some more thorough blinded testing of the WPI too - that would seem to be the easiest way to sort this out for sure (although we'd need larger numbers than those used for the BWG testing released last Oct). (This has been going on for so long!!)

It's not over, but I don't think we can look at all the publicly available data and act like it's likely the WPI's finding is going to hold up.

Click to expand...

It's becoming less likely, but a lot of the greatest advances in science have been met with lots of controversy. At the moment I am seeing a shift: first it was contamination, but I see more and more articles and papers popping up that are claiming XMRV is a real, replicating virus (not saying anything about association with disease).

Looking at the authors of the Levy study - Peterson was not part of it. According to the article he asked Levy to do the study but Kogelnik -a physician associated with Dr. Montoya at Stanford - supplied the patients.

The Science editorial staff doesn't live in a vacuum, and could easily be aware that Lipkin is slated to be a de facto referee of all this. So it seems odd that with this pending they would make a move like this.

The Science editorial staff doesn't live in a vacuum, and could easily be aware that Lipkin is slated to be a de facto referee of all this. So it seems odd that with this pending they would make a move like this.

Click to expand...

Yeah, it does.

It could be that the PR approach of the WPI and Mikovits has meant that Science are keener to distance themselves from the initial paper than they would have been otherwise. It could have left them feeling that they wanted to take some public action prior to the Lipkin results, so that they don't get criticised if Lipkin comes back showing that the WPI were wrong.

The Science editorial staff doesn't live in a vacuum, and could easily be aware that Lipkin is slated to be a de facto referee of all this. So it seems odd that with this pending they would make a move like this.

Click to expand...

Maybe the Science editors are firmly sitting themselves on the fence, in preparation for the results of the Lipkin study, so that they don't look too stupid whatever the results. If Lipkin's study confirms the WPI's work, then Science gets the glory for publishing the original study, but if Lipkin's study does not bring a result, then the Science editors can say that they had already raised a large question about the paper.

Maybe the Science editors are firmly sitting themselves on the fence, in preparation for the results of the Lipkin study, so that they don't look too stupid whatever the results. If Lipkin's study confirms the WPI's work, then Science gets the glory for publishing the original study, but if Lipkin study does not bring a result, then the Science editors can say that they had already raised a large question about the paper.

Click to expand...

Yes, I think this is it. They win both ways... it would be pretty smart to do. And I am sure a journal like Science is worried about their reputation.

It's not over, but I don't think we can look at all the publicly available data and act like it's likely the WPI's finding is going to hold up.

It would be interesting to hear Ruscetti's thoughts on all this.

I wish we had some more thorough blinded testing of the WPI too - that would seem to be the easiest way to sort this out for sure (although we'd need larger numbers than those used for the BWG testing released last Oct). (This has been going on for so long!!)

Click to expand...

Hardly. Show me some studies that have been actual replications of the original Science paper that are negative and we'll talk. How many so far to date? Ah, that's right. Zero.

The retrovirus XMRV (xenotropic murine leukemia virusrelated virus) has been detected in human prostate tumors and in blood samples from patients with chronic fatigue syndrome, but these findings have not been replicated. We hypothesized that an understanding of when and how XMRV first arose might help explain the discrepant results. We studied human prostate cancer cell lines CWR22Rv1 and CWR-R1, which produce XMRV virtually identical to the viruses recently found in patient samples, as well as their progenitor human prostate tumor xenograft (CWR22) that had been passaged in mice. We detected XMRV infection in the two cell lines and in the later passage xenografts, but not in the early passages. In particular, we found that the host mice contained two proviruses, PreXMRV-1 and PreXMRV-2, which share 99.92% identity with XMRV over >3.2-kilobase stretches of their genomes. We conclude that XMRV was not present in the original CWR22 tumor but was generated by recombination of two proviruses during tumor passaging in mice. The probability that an identical recombinant was generated independently is negligible (~1012); our results suggest that the association of XMRV with human disease is due to contamination of human samples with virus originating from this recombination event.

"After the reports of XMRV in human prostate cancer, and later of XMRV in people with CFS, retrovirologists all over the world were excited to explore its role in human infection and disease. The results published today are not what we would have expected, but due to the time and resources dedicated to the understanding of this virus by researchers at NCI and NIH as well as others, scientists can now concentrate on identifying the real causes of these diseases," said Pathak.

The retrovirus XMRV (xenotropic murine leukemia virusrelated virus) has been detected in human prostate tumors and in blood samples from patients with chronic fatigue syndrome, but these findings have not been replicated. We hypothesized that an understanding of when and how XMRV first arose might help explain the discrepant results. We studied human prostate cancer cell lines CWR22Rv1 and CWR-R1, which produce XMRV virtually identical to the viruses recently found in patient samples, as well as their progenitor human prostate tumor xenograft (CWR22) that had been passaged in mice. We detected XMRV infection in the two cell lines and in the later passage xenografts, but not in the early passages. In particular, we found that the host mice contained two proviruses, PreXMRV-1 and PreXMRV-2, which share 99.92% identity with XMRV over >3.2-kilobase stretches of their genomes. We conclude that XMRV was not present in the original CWR22 tumor but was generated by recombination of two proviruses during tumor passaging in mice. The probability that an identical recombinant was generated independently is negligible (~1012); our results suggest that the association of XMRV with human disease is due to contamination of human samples with virus originating from this recombination event.

It's becoming less likely, but a lot of the greatest advances in science have been met with lots of controversy. At the moment I am seeing a shift: first it was contamination, but I see more and more articles and papers popping up that are claiming XMRV is a real, replicating virus (not saying anything about association with disease).

Click to expand...

The cohort issue is still part of the problem- no matter how much people try and keep it a wallflower in the dance, and the fact the great and eminent scientists/retrovirologists who know all about AIDS and so forth can't get their heads around this does not instill confidence in their ability to solve the problem.

what if peterson brought levy the reagents used in wpi's original testing...and levy found them to be contaminated?

why else would peterson have done this study w/levy unless he was po'd abt the way he was treated by wpi or he really believed there was malfeasance in the original study (contamination of reagents?)

whatever ppl may think of peterson today, he has given his life-career to helping ppl with me/cfs....his motivation would be very different then a mcClure, wessley, coffin, switzer in this research. (unless driven by sour grapes)

hope things pan out for WPI but it's getting more and more difficult to keep the faith.

Yes, I think this is it. They win both ways... it would be pretty smart to do. And I am sure a journal like Science is worried about their reputation.

Click to expand...

Perhaps they win with critics of Judy M and WPI, but IMHO, they don't win when it comes to acting in a professional manner. They clearly state:

The U.S. National Institutes of Health is sponsoring additional carefully designed studies to ascertain whether the association between XMRV and CFS can be confirmed. Science eagerly awaits the outcome of these further studies and will take appropriate action when their results are known.

Click to expand...

Why would they be asking for a retraction if they are clearly saying the jury is still out? I don't get it. Just seems really bizarre. The best answer I can come up with is they're calling for this retraction because they're feeling some heat. But if that's the case, then they need to get a little backbone and let the science play out so everybody can be in agreement with the final outcome.

I think you really have to be careful with this slant Eric. Suggesting that Dr. Peterson who has focused on CFS patients for over 30 years - would torpedo a study that could benefit them simply to get back at the WPI just doesn't make sense to me .....Dr. Peterson is very well liked by his patients and his peers and has been for a long time. It's far easier for me to believe, given negative study after negative study, that the WPI is simply wrong rather than that Dr. Peterson has lost his integrity..

Dr. Levy is in the picture as well. By implicating Dr. Peterson in that manner you're also suggesting that one of the top HIV specialists in the world - a man who co-discovered HIV - somehow doesn't know how to follow the WPI's published culture procedures or do a culture test - and he is also trying to get back at them - even though he has no connection to the WPI.

The best explanation for me is that they did their best and they didn't find it. Everybody has a stake in getting this right- they all know that the Lipkin and BWG and other studies are coming up and that this issue will definitively solved at some point. Somebody is going to be proved very, very wrong in the end - because of that they all have a big stake in doing their studies correctly and determining the best they can if XMRV is or is not there.

It just doesn't make sense that anyone would try and sabotage XMRV because the truth will come out in the long run.

Click to expand...

Cort, i think we also have to see that more or less nothing has seemed to make sense in the entire XMRV/MRV story so far. You could even say nothing in ME/CFS has ever made much sense.

I agree it would not make sense and please be careful as well to realize i did not try to come up with an explanation for why Peterson did what he did. I think it's better not to speculate too much and leave blanks where there are blanks.

But i still think if Peterson, at the point where he could see they are not finding the virus, did not try to establish this exchange, this was a mistake that can hardly be explained. And it could have extreme consequences for this research and all the patients, so it's serious. Can you give me a good reason why it would have been ok to not do this? Especially if ones sees that everybody who so far reported positive results did so after contacting the WPI. This only leaves two likely conclusions, in my mind.

a) The WPI has some knowledge that is needed to find the virus and is not easy to find out for yourself
b) The WPI's methodology will produce false positives, through contamination or another way

So i think you need to contact them and let them share their knowledge with you so that you can either find the virus or show that b) is correct.

Many people have been well liked. I don't say i can explain what's going on, i've said many times it seems strange, but i can see danger and possible actions that are not right.

They have sequenced their findings in different labs around the world. So what they found was XMRV and not some mouse DNA or not (i really don't know, it's not a rhetorical question)? Also they have taken many other steps to check for contamination. Given this, does it really make more sense to you that there is contamination and they just can't find it after so long than that the negative papers are wrong?

I don't say all the negative papers are part of a conspiracy. But are the authors of the positive ones incompetent or liars? I don't think it's enough to come up with 0/0 and say "case closed", even if you are an experienced researcher, given all the other facts. Why not contact the WPI and ask for their help? Is that asked too much? And it would seem like an intelligent thing to do.

Hi, I don't want to go back over old issues, which have been discussed at length, but I don't think anything will be resolved until some time after the BWG and Lipkin studies. If they both confirm or refute the association, we have our answer. Either result is a good result for research.

The worst result comes in two forms. If BWG gets one result and Lipkin another, there is a problem. Alternatively, if either or both have ambiguous results, there is again a problem. Let us hope they can answer the issue definitively.

Please note that even if XMRV association is disproved, the cytokine signature found by WPI may still be important. Of additional interest is the improvement we see in some patients on antiretrovirals. If it is not XMRV, what are they are responding to? Is it another virus, or some other drug-biochemistry interaction? Or is it just isolated cases of improvement?

Of course, if Lipkin and BWG support the Lombardi findings, then we still have a long road to go to prove causation.

In my opinion the WPI should not even consider changing course until after the Lombardi study. They might finally be validated, and this is too important an issue to drop without solid evidence they are wrong.

My nightmare is that they will lose funding if they pull back and drop XMRV, and when I am finally relegated to a nursing home in a decade or two I will read in the paper (enews?) that XMRV was right all along. We need to know, not just have maybes to think about. Its up to the science, one way or the other, not journalistic or populist opinion.